Dataset Information

Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis.

ABSTRACT: Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a fatal disease with no available disease-modifying therapies. While pathogenic TTR mutations (TTRm) destabilize TTR tetramers, the T119M variant stabilizes TTRm and prevents disease. A comparison of potency for leading TTR stabilizers in clinic and structural features important for effective TTR stabilization is lacking. Here, we found that molecular interactions reflected in better binding enthalpy may be critical for development of TTR stabilizers with improved potency and selectivity. Our studies provide mechanistic insights into the unique binding mode of the TTR stabilizer, AG10, which could be attributed to mimicking the stabilizing T119M variant. Because of the lack of animal models for ATTR-CM, we developed an in vivo system in dogs which proved appropriate for assessing the pharmacokinetics-pharmacodynamics profile of TTR stabilizers. In addition to stabilizing TTR, we hypothesize that optimizing the binding enthalpy could have implications for designing therapeutic agents for other amyloid diseases.

SUBMITTER: Miller M

PROVIDER: S-EPMC6276790 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis.

Miller Mark M Pal Arindom A Albusairi Wabel W Joo Hyun H Pappas Beverly B Haque Tuhin Md Tariqul MT Liang Dengpan D Jampala Raghavendra R Liu Fang F Khan Jared J Faaij Marjon M Park Miki M Chan William W Graef Isabella I Zamboni Robert R Kumar Neil N Fox Jonathan J Sinha Uma U Alhamadsheh Mamoun M

Journal of medicinal chemistry 20180822 17

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a fatal disease with no available disease-modifying therapies. While pathogenic TTR mutations (TTRm) destabilize TTR tetramers, the T119M variant stabilizes TTRm and prevents disease. A comparison of potency for leading TTR stabilizers in clinic and structural features important for effective TTR stabilization is lacking. Here, we found that molecular interactions reflected in better binding enthalpy may be critical for development of TTR s ...[more]

PMID: 30133284

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Project description:AimsCardiac transthyretin amyloidosis (ATTR-CM) is a progressive and fatal condition. Prognosis can be determined at diagnosis according to the National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR) stage. We sought to examine how NAC ATTR stage changes during follow-up and whether it maintains its prognostic value throughout the disease course.Methods and resultsWe performed a retrospective study of 945 patients with wild-type ATTR-CM (wtATTR-CM) or hereditary ATTR-CM associated with the V122I variant (V122I-hATTR-CM) who were diagnosed and serially evaluated at the UK NAC. Patients who commenced any disease-modifying therapy for amyloidosis were censored at the time of doing so. Landmark Kaplan-Meier survival analyses were performed at diagnosis (n = 945) and at 6 ± 1 (n = 432), 12 ± 3 (n = 562), and 24 ± 3 (n = 316) months and stratified by recalculated NAC ATTR stage at the relevant time point. Cox regression analyses were performed to assess the prognostic significance during follow-up of an increase in NAC ATTR stage from Stage I at diagnosis. Mortality in ATTR-CM was predicted by NAC ATTR stage at each time point [Stage II vs. I, hazard ratios (HRs) 1.95-2.67; P < 0.001; Stage III vs. II, HRs 1.64-2.25; P < 0.001-0.013]. An increase from NAC ATTR Stage I, which occurred in 21%, 32%, and 44% of evaluable patients at 6, 12, and 24 months of follow-up respectively, was highly predictive of ongoing mortality at each time point (HRs 2.58-3.22; P < 0.001) and in each genotypic subgroup (HRs 1.86-4.38; P < 0.05). Increase in NAC ATTR stage occurred earlier in V122I-hATTR-CM than in wtATTR-CM (43% vs. 27% at 12 months of follow-up; P = 0.003).ConclusionsNational Amyloidosis Centre ATTR stage predicts ongoing survival throughout the disease natural history in ATTR-CM, and an increase from NAC ATTR Stage I at diagnosis to a higher NAC ATTR stage predicts mortality throughout follow-up. Serial calculation of NAC ATTR stage suggests a more aggressive phenotype in V122I-hATTR-CM than in wtATTR-CM.

Dataset Information

Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis.

Publications

Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis.

Similar Datasets

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